The treatment of acute lymphoblastic leukemia (ALL) has dramatically changed over the past three decades. However, relapsed and/or refractory ALL still remains with a very low survival and high morbidity associated with its treatment. Here, we will review the outstanding progress that has been made in the treatment of relapsed and/or refractory ALL and discuss future directions and challenges that require further investigation.

Purpose: Relapsed T-acute lymphoblastic leukemia (T-ALL) has limited treatment options. We investigated mechanisms of resistance to BH3 mimetics in T-ALL to develop rational combination strategies. We also looked at the preclinical efficacy of NWP-0476, a novel BCL-2/BCL-xL inhibitor, as single agent and combination therapy in T-ALL. Experimental Design: We used BH3 profiling as a predictive tool for BH3 mimetic response in T-ALL. Using isogenic control, venetoclax-resistant (ven-R) and NWP-0476-resistant (NWP-R) cells, phosphokinase array was performed to identify differentially regulated signaling pathways. Results: Typical T-ALL cells had increased dependence on BCL-xL, whereas early T-precursor (ETP)-ALL cells had higher BCL-2 dependence for survival. BCL-2/BCL-xL dual inhibitors were effective against both subtypes of T-lineage ALL. A 71-protein human phosphokinase array showed increased LCK activity in ven-R cells, and increased ACK1 activity in ven-R and NWP-R cells. We hypothesized that pre-TCR and ACK1 signaling pathways are drivers of resistance to BCL-2 and BCL-xL inhibition, respectively. First, we silenced LCK gene in T-ALL cell lines, which resulted in increased sensitivity to BCL-2 inhibition. Mechanistically, LCK activated NF-κB pathway and the expression of BCL-xL. Silencing ACK1 gene resulted in increased sensitivity to both BCL-2 and BCL-xL inhibitors. ACK1 signaling upregulated AKT pathway, which inhibited the pro-apoptotic function of BAD. In a T-ALL patient-derived xenograft model, combination of NWP-0476 and dasatinib demonstrated synergy without major organ toxicity. Conclusions: LCK and ACK1 signaling pathways are critical regulators of BH3 mimetic resistance in T-ALL. Combination of BH3 mimetics with tyrosine kinase inhibitors might be effective against relapsed T-ALL.

Familial platelet disorder (FPD) is associated with germline RUNX1 mutations, establishing a preleukemic state and increasing the risk of developing leukemia. Currently, there are no intervention strategies to prevent leukemia progression. Single-cell RNA sequencing ( n = 10) combined with functional analysis of samples from patients with RUNX1 -FPD ( n > 75) revealed that FPD hematopoietic stem and progenitor cells (HSPCs) displayed increased myeloid differentiation and suppressed megakaryopoiesis because of increased activation of prosurvival and inflammatory pathways. Bone marrow from patients with RUNX1 -FPD contained an elevated cytokine milieu, exerting chronic inflammatory stress on HSPCs. RUNX1 -FPD HSPCs were myeloid biased, had increased self-renewal, and were resistant to inflammation-mediated exhaustion. The bone marrow from patients with RUNX1 -FPD showed high transcript and protein expression of CD74 at the preleukemic stage compared with that of healthy controls, which remained high upon patient transformation into leukemia. Further, CD74-mediated signaling was exaggerated in RUNX1 -FPD HSPCs compared with healthy controls, leading to the activation of mTOR and JAK/STAT pathways with increased cytokine production. Genetic and pharmacological targeting of CD74 with ISO-1 and its downstream targets JAK1/2 and mTOR reversed RUNX1 -FPD differentiation defects in vitro and in vivo and reduced inflammation. Our results highlight that inflammation is an early event in RUNX1 -FPD pathogenesis, and CD74 signaling is one of the drivers of this inflammation. The repurposing of JAK1/2i (ruxolitinib) and mTORi (sirolimus) and promoting the advancement of CD74 inhibitors in clinical settings as an early intervention strategy would be beneficial to improve the phenotype of patients with RUNX1 -FPD and prevent myeloid progression.

TP53-mutant acute lymphoblastic leukemia (ALL) in adults is a high-risk subtype with poor outcomes, yet its molecular landscape and clinical implications remain incompletely defined. In this multi-institutional study of 830 adult ALL patients treated at eight academic centers between 2010 and 2024, we demonstrated that TP53 mutations are independent predictors of inferior overall survival in both B-ALL (median, 1.9 vs 5 years) and T-ALL (1.6 vs 9.5 years), irrespective of age, biologic disease subtype, or therapy. Genomic profiling revealed that >90% of TP53 mutations were DNA-binding domain missense variants, frequently co-occurring with hypodiploidy in B-ALL and NOTCH1/FBXW7 mutations in T-ALL. Unlike myeloid malignancies, biallelic TP53 mutations did not worsen outcomes, and variant type (missense vs truncating) did not influence survival. TP53-mutant B-ALL exhibited higher CD20 positivity than TP53-wild type B-ALL (65% vs 31%) but had inferior responses to conventional chemotherapy. Novel immunotherapies (e.g., inotuzumab/blinatumomab) or venetoclax-containing combination regimens improved remission rates, yet relapses were common, often with CD19/CD20/CD22 loss (triple-negative) or acquisition of new mutations. Allogeneic transplantation in first remission trended toward survival benefit (median, 3.3 vs 2.2 years). These findings underscore TP53-mutant ALL as a distinct, chemo-resistant entity necessitating tailored approaches, with antigen escape highlighting challenges of immunotherapy durability.

Adolescents and young adults (AYAs) diagnosed with cancer are an age-defined population, with studies reporting up to 45% of the population experiencing psychological distress. Although it is essential to screen and monitor for psychological distress throughout AYAs’ cancer journeys, many cancer centers fail to effectively implement distress screening protocols largely due to busy clinical workflow and survey fatigue. Recent advances in mobile technology and speech science have enabled flexible and engaging methods to monitor psychological distress. However, patient-centered research focusing on these methods’ feasibility and acceptability remains lacking. Therefore, in this project, we aim to evaluate the feasibility and acceptability of an artificial intelligence (AI)-enabled and speech-based mobile application to monitor psychological distress among AYAs diagnosed with cancer. We use a single-arm prospective cohort design with a stratified sampling strategy. We aim to recruit 60 AYAs diagnosed with cancer and to monitor their psychological distress using an AI-enabled speech-based distress monitoring tool over a 6 month period. The primary feasibility endpoint of this study is defined by the number of participants completing four out of six monthly distress assessments, and the acceptability endpoint is defined both quantitatively using the acceptability of intervention measure and qualitatively using semi-structured interviews.

Background: Cognitive behavioral therapy (CBT) has been successfully utilized in improving mental health (MH) and quality of life (QoL) in the general population, regardless of age. Cancer, which is most frequently diagnosed in older adults, is a debilitating illness that has a detrimental and long-lasting effect on patients’ MH and QoL. While numerous studies have demonstrated CBT’s efficacy, little evidence exists for its role in older cancer patients. This study, using MH and QoL metrics, evaluates the effectiveness of CBT for older adult cancer patients. Methods: Focusing on MH and QoL and an average age of over 60 years old, a final analysis was performed on 17 clinical trials with a total of 124 effect sizes, including 3073 participants receiving CBT. “Metaphor” and “Robumeta” packages in R Statistical Software (version 4.2.2) were used for analysis, which included robust variance estimation (RVE) in intercept-only meta-regression, and univariate meta-regression for moderator analysis. Results: With 17 clinical trials and 124 effect sizes, our results show that CBT moderately improves MH and QoL in cancer patients d = 0.19, 95% CI 0.0166–0.364, p < 0.0399. The delivery format was shown to be a strong moderator of CBT effectiveness with interpersonal technological interventions combined with pre-programmed segments having a very strong treatment effect size (d = 1.7307, 95% CI 1.5244–1.937, p < 0.001). Conclusions: The use of CBT in older adult cancer patients statistically improves MH and QoL, with delivery format and stages of treatment having important roles. Tech-only interpersonal interventions combined with pre-programmed CBT provide an avenue for targeting older adult cancer patients.